Microbe recognition based on a small collection of germline-encoded receptors carries a hidden liability: the possibility that mutational changes in the proteome will lead to self-recognition. The risk of self-recognition is enhanced, because innate immune receptors display low specificity, as they are driven to accommodate heterogeneous signature molecules found in the microbial world. The proteome structure is globally constrained by the innate immune sensing apparatus to satisfy a proscription against self-reactivity. But accidents happen, and here it is proposed that mutations creating neo-ligands for innate immune receptors are the proximal cause of sterile inflammatory diseases, which in turn embody the selective pressure that constrains the proteome. Such mutations are predictably dominant and may occur in the germline and also in somatic cells (e.g. in lymphocytes), causing inflammatory effects upon clonal expansion. They may also account for the inflammatory character of selected neoplastic diseases. The neo-ligand hypothesis accounts for the heritability, ambiguous linkage characteristics, phenotypic heterogeneity, and natural history of diverse forms of sterile inflammation. It explains sterile inflammatory diseases as conditions in which aberrant immune signaling is caused by proteome encroachment upon the ligand-recognition space over which the innate immune system stands guard.